International Transporter Consortium Commentary on Clinically Important Transporter Polymorphisms

Giacomini, Kathleen M.; Balimane, Praveen; Cho, S. K.; Eadon, Michael T.; Edeki, Timi; Hillgren, Kathleen M.; Huang, Shiew‐Mei; Sugiyama, Yuichi; Weitz, Dietmar; Wen, Yujia; Xia, Cindy Q.; Yee, Sook Wah; Zimdahl, Heike; Niemi, Mikko

doi:10.1038/clpt.2013.12

Cited by 148 publications

(146 citation statements)

References 10 publications

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“…We did not find this polymorphism to affect rifabutin exposure; however, our study included insufficient carriers of this polymorphism to exclude an association. While rs4149056 is more frequent in Asian and Caucasian populations than in other populations, the low frequency of this SNP in our study (Table 1) is consistent with the reported population frequency (0.7 to 11.5%) in sub-Saharan Africa (21).…”

supporting

confidence: 80%

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

Hennig

Naiker

Reddy

et al. 2016

Antimicrob Agents Chemother

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f Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.) R ifabutin is an alternative rifamycin for tuberculosis treatment. It is also used to treat other mycobacterial infections and to prevent Mycobacterium avium complex in patients with AIDS. Unlike rifampin, rifabutin does not reduce concentrations of concomitantly administered protease inhibitors (PIs) significantly (1). The pharmacokinetics of rifabutin are highly varied (2-4). As a CYP3A4 substrate, rifabutin is subject to drug interaction with CYP3A4 inhibitors, such as PIs, and increases in exposure can result in an increased risk for adverse effects, particularly uveitis. Toxicity, including uveitis, neutropenia, and hepatotoxicity, are a concern with high exposures (5). Conversely, low rifabutin exposures are associated with relapse and acquired rifamycin resistance (6). While therapeutic drug monitoring is advocated, it is seldom available (5). Although a lack of suitable formulations and cost limit the widespread use of the drug in resource-constrained settings, its use in combination with PIs is increasing as antiretroviral therapy (ART) programs mature and more patients are started on 2nd-line PI-based regimens.In a process subject to autoinduction, arylacetamide deacetylase converts rifabutin to the active primary metabolite 25-desacetyl rifabutin, which is in turn metabolized by CYP3A4 (7,8). Organic anion-transporting polypeptide 1B1 (OATP1B1) mediates hepatocellular influx of diverse xenobiotics prior to their excretion in bile (9). Functional single nucleotide polymorphisms (SNPs) in SLCO1B1, the gene encoding OATP1B1, have been associated with significant alterations in drug pharmacokinetics. SLCO1B1 rs4149032 and rs11045819 have been associated with lower rifampin and lopinavir concentrations (10-12), while the rs4149056 SNP is associated with higher concentrations of lopinavir and other drugs, including statins (13,14). The SLCO1B1 rs2306283 variant is associated with increased OATP1B1 expression (15). The allele frequencies of SLCO1B1 vary markedly between different populations (16). We recently showed that SLCO1B1 rs4149032 is carried by 70% of South Africans, in whom its presence predicts reduced rifampin concentrations (10). Since little is known about pharmacogenomic determinants of rifabutin exposure, we investigated the frequencies of SLCO1B1 SNPs rs4149032, rs11045819, rs4...

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supporting

confidence: 80%

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

Hennig

Naiker

Reddy

et al. 2016

Antimicrob Agents Chemother

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“…The assessment of OATP1B-mediated DDIs with certain chemotypes (e.g., anionic small molecule drug candidates) has become a critical aspect of early drug development as recognized in draft guidance issued by the regulatory agencies in the United States (U.S. Food and Drug Administration Center for Drug Evaluation and Research, 2012; http:// www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/ucm292362.pdf), the European Union (Committee for Human Medicinal Products, 2012; http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2012/07/WC500129606.pdf) and the International Transporter Consortium (Giacomini et al, 2013;Tweedie et al, 2013). These guidance documents/perspectives acknowledge OATP1B1 and OATP1B3 as two of the seven clinically relevant transporters and provide basic methodology toward the prediction of the DDI magnitude with OATP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The magnitude of DDI arising via inhibition for OATP1B1-mediated hepatic uptake (R value) by FA was calculated using eq. 7 (Giacomini et al, 2013;Tweedie et al, 2013): where K i would represent the inhibition constant for OATP1B1 by FA and I in, max,u represents the estimated maximum unbound FA concentration at the inlet to the liver and is defined as follows (Ito et al, 2002).…”

Section: Methodsmentioning

confidence: 99%

The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy

Eng

Scialis

Rotter

et al. 2016

Drug Metabolism and Disposition

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Chronic treatment of methicillin-resistant Staphylococcus aureus strains with the bacteriostatic agent fusidic acid (FA) is frequently associated with myopathy including rhabdomyolysis upon coadministration with statins. Because adverse effects with statins are usually the result of drug-drug interactions, we evaluated the inhibitory effects of FA against human CYP3A4 and clinically relevant drug transporters such as organic anion transporting polypeptides OATP1B1 and OATP1B3, multidrug resistant protein 1, and breast cancer resistance protein, which are involved in the oral absorption and/or systemic clearance of statins including atorvastatin, rosuvastatin, and simvastatin. FA was a weak reversible (IC 50 = 295 6 1.0 mM) and time-dependent (K I = 216 6 41 mM and k inact = 0.0179 6 0.001 min 21) inhibitor of CYP3A4-catalyzed midazolam-19-hydroxylase activity in human liver microsomes. FA demonstrated inhibition of multidrug resistant protein 1-mediated digoxin transport with an IC 50 value of 157 6 1.0 mM and was devoid of breast cancer resistance protein inhibition (IC 50 > 500 mM). In contrast, FA showed potent inhibition of OATP1B1-and OATP1B3-specific rosuvastatin transport with IC 50 values of 1.59 mM and 2.47 mM, respectively. Furthermore, coadministration of oral rosuvastatin and FA to rats led to an approximately 19.3-fold and 24.6-fold increase in the rosuvastatin maximum plasma concentration and area under the plasma concentration-time curve, respectively, which could be potentially mediated through inhibitory effects of FA on rat Oatp1a4 (IC 50 = 2.26 mM) and Oatp1b2 (IC 50 = 4.38 mM) transporters, which are responsible for rosuvastatin uptake in rat liver. The potent inhibition of human OATP1B1/OATP1B3 by FA could attenuate hepatic uptake of statins, resulting in increased blood and tissue concentrations, potentially manifesting in musculoskeletal toxicity.

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“…Such observations also suggest that interindividual differences in BCRP function due to pharmacogenetics likely contribute to variability in bioavailability (absorption), exposure [area under the plasma concentrationtime curve (AUC) and maximum plasma concentration (C max )], and efficacy of drugs that are BCRP substrates (Giacomini et al, 2010(Giacomini et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

“…The important role that BCRP plays in drug disposition has been demonstrated clinically in pharmacogenetic studies investigating the ABCG2 single nucleotide polymorphism c.421C.A (Q141K, rs2231142), in which the impaired transport function phenotype (421CA or AA) resulted in increased plasma exposures of several BCRP substrate drugs, including rosuvastatin, atorvastatin, fluvastatin, and diflomotecan (Sparreboom et al, 2004;Keskitalo et al, 2009;Giacomini et al, 2013). Such observations also suggest that interindividual differences in BCRP function due to pharmacogenetics likely contribute to variability in bioavailability (absorption), exposure [area under the plasma concentrationtime curve (AUC) and maximum plasma concentration (C max )], and efficacy of drugs that are BCRP substrates (Giacomini et al, 2010(Giacomini et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

Elsby

Martín

Surry

et al. 2015

Drug Metabolism and Disposition

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The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC 50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC 50 > 10 mM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and C max , respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC 50 ) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17b-glucuronide. Calculated parameters of maximum enterocyte concentration [I gut max ], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC 50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant statin dose adjustment in clinical practice.

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International Transporter Consortium Commentary on Clinically Important Transporter Polymorphisms

Cited by 148 publications

References 10 publications

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

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